Morichika Toshihiko, Takahashi Hideo K, Iwagaki Hiromi, Yagi Takahito, Saito Shinnya, Kubo Shinichiro, Yoshino Tadashi, Akagi Tadaatsu, Mori Shuji, Nishibori Masahiro, Tanaka Noriaki
Department of Gastroenterological Surgery and Transplant, Okayama University Graduate School of Medicine and Dentistry, Okayama City, Japan.
Transplantation. 2003 Jun 27;75(12):2100-5. doi: 10.1097/01.TP.0000066580.49583.B3.
The elevation of plasma interleukin (IL)-18 levels and the expression of intercellular adhesion molecule (ICAM)-1 and B7 on monocytes are involved in acute rejection. Prostaglandin (PG) E2 suppresses the rejection in animal transplantation models; however, little is known about its action mechanism. We examined the effect of PGE2 on the expression of ICAM-1 and B7 in the human mixed leukocyte reaction (MLR) in the presence or absence of IL-18.
We measured the expression of ICAM-1, B7.1, and B7.2 on human monocytes by flow cytometry and determined the associated production of interferon-gamma and IL-12 by enzyme-linked immunosorbent assay. The modulatory effects of PGE2 and the relevant PGE2 receptor subtypes were characterized pharmacologically.
PGE2 inhibited the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR in a concentration-dependent manner. Whereas IL-18 significantly induced the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR and the production of interferon-gamma and IL-12, PGE2 inhibited these IL-18-initiated enhancements. The effects of PGE2 were mimicked by selective EP2 and EP4 agonists, but not by EP1 and EP3 agonists.
PGE2 strongly inhibited MLR with respect to the expression of ICAM-1, B7.1, and B7.2 via the EP2 and EP4 receptors, irrespective of the presence or absence of IL-18. In the previous study, histamine inhibited ICAM-1 expression in the presence of IL-18 but had no effect in the absence of IL-18. These results indicate that the inhibitory effect of PGE2 may be more general and stronger than that of histamine and may play an important role in future immunosuppressive strategies.
血浆白细胞介素（IL）-18水平升高以及单核细胞上细胞间黏附分子（ICAM）-1和B7的表达与急性排斥反应有关。前列腺素（PG）E2在动物移植模型中可抑制排斥反应；然而，其作用机制尚不清楚。我们研究了在有或无IL-18存在的情况下，PGE2对人混合淋巴细胞反应（MLR）中ICAM-1和B7表达的影响。
我们通过流式细胞术检测人单核细胞上ICAM-1、B7.1和B7.2的表达，并通过酶联免疫吸附测定法测定相关的γ干扰素和IL-12的产生。从药理学角度对PGE2及相关PGE2受体亚型的调节作用进行了表征。
PGE2以浓度依赖的方式抑制MLR中单核细胞上ICAM-1、B7.1和B7.2的表达。虽然IL-18显著诱导MLR中单核细胞上ICAM-1、B7.1和B7.2的表达以及γ干扰素和IL-12的产生，但PGE2抑制了这些由IL-18引发的增强作用。选择性EP2和EP4激动剂可模拟PGE2的作用，但EP1和EP3激动剂则不能。
无论有无IL-18，PGE2均可通过EP2和EP4受体强烈抑制MLR中ICAM-1、B7.1和B7.2的表达。在先前的研究中，组胺在有IL-18存在时可抑制ICAM-1的表达，但在无IL-18时则无作用。这些结果表明，PGE2的抑制作用可能比组胺更普遍、更强，并且可能在未来的免疫抑制策略中发挥重要作用。
